文章：

HADHA通过加速MDM2介导的p53泛素化促进胶质瘤进展

HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination 

原文发布日期：2024-07-22 

英文摘要：

Glioma represents a notoriously aggressive and malignant tumor that targets the central nervous system, with a poor prognosis for patients. In this research, we set out to examine the role of hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA) in glioma, its clinical significance, as well as its potential biological mechanisms. In this study, we used immunohistochemistry staining to assess the expression level of HADHA in glioma tissues. We also evaluated the correlation between HADHA expression and patient survival using the Kaplan–Meier method. To determine the role of HADHA in glioma cells, we conducted loss-of-function assays in vitro and in vivo. Additionally, we utilized co-immunoprecipitation and protein stability assays to investigate the potential mechanisms involving HADHA, MDM2, and p53 in glioma. Our research findings indicate that gliomas exhibit high levels of HADHA. Clinically, high expression of HADHA suggests an increased risk of malignant tumors, recurrence, and reduced survival rates. Functionally, knocking down HADHA can lead to decreased proliferation, enhanced apoptosis, and inhibited migration of glioma cells. Mechanistically, HADHA accelerates MDM2-mediated p53 ubiquitination through interaction with MDM2. Consistently, MDM2 knockdown or overexpression of p53 can attenuate the promoting effect of HADHA overexpression on the malignant progression of glioma. We have discovered a novel role of HADHA in promoting MDM2-mediated p53 ubiquitination, which contributes to the progression of glioma. This finding provides a new perspective to understand the pathogenesis of glioma and offers a potential target for developing innovative therapeutic strategies. 

摘要翻译：

胶质瘤是一种以中枢神经系统为靶点的侵袭性强、恶性程度高的肿瘤，患者预后较差。本研究旨在探讨羟基酰基辅酶A脱氢酶三功能多酶复合体亚基α（HADHA）在胶质瘤中的作用、临床意义及其潜在生物学机制。我们采用免疫组化染色技术评估HADHA在胶质瘤组织中的表达水平，并通过Kaplan-Meier法分析HADHA表达与患者生存率的相关性。为探究HADHA在胶质瘤细胞中的功能，我们开展了体外和体内功能缺失实验。此外，通过免疫共沉淀和蛋白质稳定性实验，我们深入研究了HADHA与MDM2、p53在胶质瘤中的潜在作用机制。研究结果表明：胶质瘤中HADHA呈现高表达特征；临床数据分析显示HADHA高表达与恶性肿瘤高风险、复发率上升及生存率降低显著相关；功能实验证实敲低HADHA可抑制胶质瘤细胞增殖、促进凋亡并减弱迁移能力；机制研究发现HADHA通过与MDM2相互作用，加速MDM2介导的p53蛋白泛素化降解。值得注意的是，敲低MDM2或过表达p53均可逆转HADHA过表达对胶质瘤恶性进展的促进作用。本研究首次揭示HADHA通过促进MDM2介导的p53泛素化降解从而驱动胶质瘤进展的新机制，这一发现为理解胶质瘤发病机制提供了新视角，并为开发创新治疗策略提供了潜在靶点。

原文链接：

HADHA promotes glioma progression by accelerating MDM2-mediated p53 ubiquitination